Phagocytes in the body play a pivotal role in innate immunity, particularly in removal of foreign substances and waste products by their phagocytosis. Phagocytes are considered to also play an important role in the modulation of acquired immunity by their antigen processing function. In contrast to these roles, it is known that acceleration of phagocyte activity or function in the body may lead to pathological conditions.
Diseases caused by acceleration of phagocyte activity or function are, for example, atherosclerosis, congestive heart failure, ischemic diseases, restenosis, hypertension, fibrotic vasculopathies (diabetes, systemic lupus erythematosus, etc.), neurodegenerative diseases (e.g., Alzheimer's disease, Huntington's disease, Parkinson's disease, spinocerebellar degeneration, amyotrophic lateral sclerosis, etc.), brain injury, cerebrovascular events (e.g., strokes, seizures, nerve injury, regeneration in the central nervous system, etc.), hematopoietic disorders, adult respiratory distress syndrome (ARDS), cancers (leukemias, particularly adult T-cell leukemia), solid cancers, autoimmune diseases, infections (e.g., HIV infection, AIDS, etc.), fibroproliferative disorders (e.g., psoriasis), chronic and acute inflammatory diseases (e.g., rheumatoid arthritis, Crohn's disease, inflammatory bowel syndrome, etc.), glomerulopathies, sepsis, graft rejection, graft versus host disease, osteopathies, cardiac and non-cardiac vascular disease states that can be characterized by aberrant fibroproliferative/inflammatory responses, for example, diseases characterized by infiltration of leukocytes at an injury site, such as oxygen- or glucose-deficient tissue resulting from the diseases (e.g., cerebral apoplexy, myocardial infarction, etc.), among others.
Phagocytes present in various tissues in the body mostly express scavenger receptors, which contribute to phagocytosis of foreign substances. Scavenger receptors are known to have an affinity to various types of particles with a negative charge and to mediate phagocytosis of LDL modified by oxidation, acetylation, glycosylation, etc. as well as of foreign bacteria in the body and their components (Non Patent Literature 1 to 3). The expression of scavenger receptors is not regulated by the amount of modified LDL taken up by phagocytes, and consequently phagocytes take up modified LDL indefinitely. Phagocytes overladen with modified LDL form foam cells in the tunica intima and then induce atherosclerosis.
Based on the above fact that atherosclerosis is induced by phagocytes overladen with modified LDL, it is considered that atherosclerosis may be effectively prevented and treated by efficient phagocyte-targeted delivery of, for example, a compound having inhibitory effect on foam cell formation (e.g., esculeogenin A (Non Patent Literature 4), a PPARγ agonist (Non Patent Literature 5), adiponectin (Non Patent Literature 6), etc.), an enzyme that metabolizes or decomposes modified LDL accumulated in phagocytes (Non Patent Literature 7), or the like. Various studies are conducted for this purpose today.
One example of conventional approaches to efficient delivery of a drug to phagocytes is use of a targeting liposome. However, the production of a targeting liposome requires a complicated chemical synthesis and purification process, and thus there are many problems in an attempt to make such a targeting liposome industrially applicable.
For these reasons, there have been demands for the development of a highly safe carrier that delivers a substance to phagocytes at a high efficiency and is easily produced at relatively low cost.